关键词: Phelan-McDermid 综合征, 22q13.3缺失综合征, SHANK3基因, 全面发育迟缓, 语言发育障碍

Abstract: Background：Phelan McDermid syndrome (PMS) is a rare neurodevelopmental disorder, and the SHANK3 gene defect has been identified as a key candidate gene for the neurological characteristics of this syndrome. Currently, no clinical diagnostic criteria have been established, and the confirmed diagnosis relies on genetic testing. Objective：To summarize the clinical phenotype and genetic characteristics of PMS and to explore the clinical diagnostic pathway of PMS. Design：Case series report. Methods：Patients diagnosed with PMS who were admitted to the Department of Child Health Care at Children's Hospital of Fudan University from January 2014 to December 2022 were included. The genotype characteristics, developmental characteristics, clinical symptoms, cranial imaging, EEG and other results were retrospectively analyzed. Literature was searched to summarize clinical diagnostic clues for PMS. Main outcome measures：Genotype and clinical phenotype. Results：A total of 42 patients were included in the analysis, including 24 males and 18 females with an average age of 3.8 (1.5-12.9)years at the first diagnosis. In this study, the most common clinical features (>50%) were global developmental delay or intellectual disability (100%), absent or severely delayed speech (100%), inattention (100%), ASD (86%), hyperactivity (82%), delayed major motor development milestones (52%). Other were facial deformities including large but poorly formed ears, full or puffy cheeks, anteverted nares, periorbital fullness, flat midface, fleshy hands/feet, bulbous nose, wide forehead or protruding forehead. The new phenotypes included sparse or absent eyebrow tail, excessive body hair, auricular deformities, drooping eye type, and ligament relaxation. Genetic testing revealed that all 42 cases were pathogenic mutations, of which 21 were 22q13.3 deletions (0.1-7.7Mb, average 3.1Mb) including the SHANK3 gene, 4 were only partial exon deletions of the SHANK3 gene, and 17 were heterozygous point mutations in the SHANK3 gene, including 12 frameshift mutations and 5 nonsense mutations. Conclusions：When there is neonatal hypotonia, significant delays in motor and language development milestones at 18 months, developmental assessments of any age or form suggesting severe developmental lag in at least five functional areas, as well as the presence of large ears disproportionate to head length and fleshy hands/feet disproportionate to body shape, it should be highly suspected that they were likely to be PMS, and further genetic testing was needed to clarify the diagnosis.

Key words: Phelan-McDermid syndrome, 22q13.3 deletion syndrome, SHANK3 gene, Global developmental delay, Language development disorders